The PTEN anti-oncogene is among the most frequently mutated genes in malignant brain tumors. Normally, PTEN is a lipid phosphatase which blocks malignant phenotypes primarily by inhibiting the PI3 Kinase/AKT pathways, but PTEN can also act as a protein phosphatase. PTEN is expressed in brain late in development, and neuronal expression continues throughout adult life. Although loss of PTEN can cause neuronal hyperplasia, little is known about the role of PTEN in neuronal development or in normal neurons. Pathways influenced by PTEN suggest that this anti-oncogene may increase neuronal sensitivity to toxicity and/or degenerative processes, which is supported by our preliminary data. This proposal will first determine whether PTEN can modulate sensitivity of cultured neuron-like cells to toxins used in models of Alzheimer's disease and Parkinson's disease. While studying this hypothesis, we have unexpectedly found that PTEN blocks NGF signaling in PC12 cells, and this appears to be at least partially due to inhibition of expression of trkA and p75 NGF receptors at the protein and mRNA levels. DNA microarray then revealed that PTEN can inhibit expression of several genes, including tyrosine hydroxylase and GTP cyclohydrolase 1. Since this may also have implications for neuronal function and for Parkinson's disease, the second Aim of this proposal will also explore the mechanism by which PTEN inhibits expression of these genes. The final Aim of this proposal will explore the effect of age and neurotoxins used in models of neurodegenerative disorders on PTEN levels and function to determine the biological relevance of data generated from the first two Aims. These studies and my development as an independent clinical scientist will be significantly advanced by Dr. M. Flint Beal, who will serve as my sponsor and who is a leading expert in neuronal degeneration in PD and AD. Additional mentoring by Dr. Eric Holland, a leading expert on anti-oncogene signal transduction, will also add significantly to my scientific growth and will also help me to realize many of the Specific Aims of this proposal. The environment at Cornell and the strong support of my institution will permit me to focus upon these studies with minimal distractions. My scientific background is substantial, and this will facilitate realization of the goal of this project. This plan outlined in this award will, however, enhance previously underserved aspects of my education while focusing on an important scientific question, in order to promote a successful transition to scientific independence.